Subarachnoid hemorrhage (SAH)-induced vasospasm is a major cause of mortality and neurological morbidity, and 5-10% of strokes are the result of SAH. Vasospasm, one of several complications after SAH, occurs in 20-40% of patients with ruptured intracranial aneurysms. Pharmacological interventions have been tried in experimental and clinical trials, but with limited success, in part because the mediators of vasomotor regulation at the level of the neurovascular unit (neurons, glia and blood vessels) are not well described. Recent work suggests that astrocytes may play a previously unrecognized role in regulating blood flow in the neurovascular unit;if this is dysregulated in the setting of SAH, it represents a novel target for the treatment of vasospasm. My goal in this proposal is to test the hypotheses that: 1) normal astrocyte calcium activity is disrupted by experimental SAH;2) vasospasm at the microcirculatory level is due, at least in part, to the abnormal astrocyte calcium activity induced by SAH;and 3) the action of known vasodilators and vasoconstrictors on cerebral microvessels is disrupted by SAH, and this is due in part of abnormal astrocyte calcium signaling. Experimental SAH will be induced in mice, and astrocyte calcium activity and blood flow through adjacent intracortical arteries will be measured in vivo using 2-photon laser scanning microscopy;this will be compared to sham-treated mice. The role of abnormal astrocyte calcium signaling in microvessel vasospasm will be determined by the caging and uncaging of calcium in astrocytes, and determining the effect on blood flow through adjacent microvessels. Lastly, the effects of traditional vasodilators and vasoconstrictors will be measured in conjunction with monitoring of astrocyte calcium levels using calcium-sensitive dyes to determine if the response at the microvessel level to traditional vasodilators and constrictors is disrupted by SAH, and whether this may be due in part of abnormal astrocyte calcium signaling. Establishing a central role for the astrocyte in SAH-induced vasospasm may provide a potential target for new clinical therapies that might prevent stroke associated with SAH.
|Plog, Benjamin A; Moll, Katherine M; Kang, Hongyi et al. (2014) A novel technique for morphometric quantification of subarachnoid hemorrhage-induced microglia activation. J Neurosci Methods 229:44-52|